Design, characterization, and evaluation of an aceclofenac cocrystal for improved solubility and stability
DOI:
https://doi.org/10.69857/joapr.v13i6.1699Keywords:
Pharmaceutical cocrystal, Aceclofenac, Solubility, In vivo, In vitro, Stability studyAbstract
Background: Co-crystallization enhances APIs by forming noncovalent interactions with coformers, thereby improving physicochemical properties. Aceclofenac was selected for its low solubility, whereas L-lysine serves as a coformer to enhance solubility and stability via hydrogen bonding. This strategy effectively improves the solubility, stability, and bioavailability of poorly soluble drugs. Methods: The aceclofenac–lysine co-crystal was synthesized using the Neat Grinding technique. The synthesized cocrystal was characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Hot stage microscopy (HSM), and Fourier transform infrared spectroscopy (FTIR). Dissolution behavior, stability, and in vivo anti-inflammatory activity were evaluated in comparison with pure aceclofenac. Results: PXRD and DSC confirmed a new crystalline phase, while FTIR revealed hydrogen bonding between aceclofenac and lysine. The cocrystal exhibited a 2.66-fold improvement in dissolution (91.84% vs. 34.41% at 90 min) and superior stability, maintaining >86% dissolution after six months at 40°C/75% RH, compared to ~30% for pure aceclofenac. In vivo studies demonstrated enhanced anti-inflammatory efficacy, with 81.50% edema inhibition versus 74.35% with the pure drug (p < 0.0001). Discussion: The ACF-lysine cocrystal achieved dissolution enhancement that maintained stability over six months, and demonstrated statistically significant improvement in anti-inflammatory efficacy, confirming superior therapeutic performance over pure aceclofenac. Conclusion: Co-crystallization with L-lysine effectively enhanced aceclofenac's biopharmaceutical and pharmacological performance. The aceclofenac-lysine co-crystal exhibited 2.66-fold faster dissolution, greater stability under accelerated storage, and significantly improved anti-inflammatory efficacy (81.50% vs. 74.35% edema inhibition; p < 0.0001) compared with pure aceclofenac. These results demonstrate the value of amino acid coformers in improving the solubility of poorly soluble drugs.
Downloads
References
Iolascon G, Gimenez S, Mogyorosi D. A review of aceclofenac: analgesic and anti-inflammatory effects on musculoskeletal disorders. J. Pain Res., 14, 3651–63 (2021) https://doi.org/10.2147/JPR.S326101
Jessica A, Wahyuni SN, Zaini E, Fitriani L. Increased dissolution rate of aceclofenac by formation of multicomponent crystals with L-glutamine. Int. J. Appl. Pharm., 16(S1), 45–52 (2024) https://doi.org/10.22159/ijap.2024.v16s1.09
Shakeel F, Al-Shdefat R, Altamimi MA, et al. Solubility and thermodynamic analysis of aceclofenac in different {Carbitol + water} mixtures at various temperatures. BMC Chem., 18, 168 (2024) https://doi.org/10.1186/s13065-024-01287-z
Kumar A, Kumar M. Improvisation of dissolution profile of aceclofenac by using cocrystallization technique. Afr. J. Biomed. Res., 27(4S), 11518–24 (2024) https://doi.org/10.53555/AJBR.v27i4S.5769
Tran P, Pyo YC, Kim DH, Lee SE, Kim JK, Park JS. Overview of the manufacturing methods of solid dispersion technology for improving the solubility of poorly water-soluble drugs and application to anticancer drugs. Pharmaceutics, 11(3), 132 (2019) https://doi.org/10.3390/pharmaceutics11030132
Luke DR, Tomaszewski K, Damle B, Schlamm HT. Review of the basic and clinical pharmacology of sulfobutylether-β-cyclodextrin (SBECD). J. Pharm. Sci., 99(8), 3291–301 (2010) https://doi.org/10.1002/jps.22109
Nurismi E, Rosaini H. Effect of different methods on the multicomponent crystal formation from medicinal natural ingredient compounds. Int. J. Pharm. Sci. Med., 6(5), 32–9 (2021) https://doi.org/10.47760/ijpsm.2021.v06i05.004
Kumar S, Gupta A, Prasad R, Singh S. Novel aceclofenac cocrystals with L-cystine: virtual coformer screening, mechanochemical synthesis, and physicochemical investigations. Curr. Drug Deliv., 18(1), 88–100 (2021) https://doi.org/10.2174/1567201817666200817110949
Sharma S, Kumar S, Gupta A, et al. Screening of aceclofenac for cocrystallization with nicotinamide: theoretical and practical perspective. Indian J. Pharm. Sci., 84(6), 1396–1405 (2022) https://doi.org/10.36468/pharmaceutical-sciences.1396
Yousef MA, Vangala VR. Pharmaceutical cocrystals: molecules, crystals, formulations, medicines. Cryst. Growth Des., 19(12), 7420–38 (2019) https://doi.org/10.1021/acs.cgd.8b01898
Grothe E, Meekes H, Vlieg E, ter Horst JH, de Gelder R. Solvates, salts, and cocrystals: a proposal for a feasible classification system. Cryst. Growth Des., 16(6), 3237–43 (2016) https://doi.org/10.1021/acs.cgd.6b00200
Kumar S, Nanda A. Pharmaceutical cocrystals: an overview. Indian J. Pharm. Sci., 79(6), 858–71 (2017) https://doi.org/10.4172/pharmaceutical-sciences.1000302
Bolla G, Sarma B, Nangia AK. Crystal engineering of pharmaceutical cocrystals in the discovery and development of improved drugs. Chem. Rev., 122(13), 11514–603 (2022) https://doi.org/10.1021/acs.chemrev.1c00987
Putri D. Review: multicomponent crystals: cinnamic acid as a co-former. Int. J. Pharm. Sci. Med., 6(1), 92–8 (2021) https://doi.org/10.47760/ijpsm.2021.v06i01.008
Afzal H, Abbas N, Hussain A, Latif S, Fatima K, Arshad MS. Physicomechanical, stability, and pharmacokinetic evaluation of aceclofenac dimethyl urea cocrystals. AAPS PharmSciTech, 22(2), 68 (2021) https://doi.org/10.1208/s12249-021-01938-7
Sharma G, Saini MK, Thakur K, Kapil N, Garg NK, Raza K. Aceclofenac cocrystal nanoliposomes for rheumatoid arthritis with better dermatokinetic attributes: a preclinical study. Nanomedicine, 12(6), 615–38 (2017) https://doi.org/10.2217/nnm-2016-0405
Kumar S, Gupta A, Prasad R, Singh S. Novel aceclofenac cocrystals with L-cystine: virtual coformer screening, mechanochemical synthesis, and physicochemical investigations. Curr. Drug Deliv., 18(1), 88–100 (2021) https://doi.org/10.2174/1567201817666200817110949
Sohrab M, Mahapatra SP, Tiwari S. Enhancement of dissolution rate of aceclofenac by formation of aceclofenac–nicotinic acid cocrystal using water-soluble polymers like PVP K-30, HPMC E5, SSG, and Na-CMC. Indo Glob. J. Pharm. Sci., 5(3), 154–70 (2015) https://doi.org/10.35652/IGJPS.2015.01
Molajafari F, Li T, Abbasichaleshtori M, et al. Computational screening for prediction of co-crystals: method comparison and experimental validation. CrystEngComm, 26, 1620–36 (2024) https://doi.org/10.1039/D3CE01252B
Neese F. The ORCA program system. Wiley Interdiscip. Rev. Comput. Mol. Sci., 2(1), 73–8 (2012) https://doi.org/10.1002/wcms.81
Neese F. Software update: the ORCA program system, version 4.0. Wiley Interdiscip. Rev. Comput. Mol. Sci., 8(1), e1327 (2018) https://doi.org/10.1002/wcms.1327
Lu T, Chen F. Multiwfn: a multifunctional wavefunction analyzer. J. Comput. Chem., 33(5), 580–92 (2012) https://doi.org/10.1002/jcc.22885
Zhang H, Zeng H, Li M, Song Y, Tian S, Xiong J, et al. Novel ascorbic acid co-crystal formulations for improved stability. Molecules, 27(22), 7998 (2022) https://doi.org/10.3390/molecules27227998
Kumar A, Nanda A. Similar but not same: impact of structurally similar coformers on co-crystallization with telmisartan. J. Pharm. Innov., 18(4), 1954–65 (2023) https://doi.org/10.1007/s12247-023-09759-w
Alenazi NA, Bokhari MG, Abourehab MAS, Abukhadra MR, El-Gendy EM, El-Sayed YM, et al. Drug polymeric carrier of aceclofenac based on amphiphilic chitosan micelles. ACS Omega, 8(50), 48145–58 (2023) https://doi.org/10.1021/acsomega.3c07065
Weng J, Wong SN, Xu X, Xuan B, Wang C, Chen R, et al. Cocrystal engineering of itraconazole with suberic acid via rotary evaporation and spray drying. Cryst. Growth Des., 19(5), 2736–45 (2019) https://doi.org/10.1021/acs.cgd.8b01873
Haneef J, Chadha R. Drug–drug multicomponent solid forms: cocrystal, coamorphous and eutectic of three poorly soluble antihypertensive drugs using a mechanochemical approach. AAPS PharmSciTech, 18, 2279–90 (2017) https://doi.org/10.1208/s12249-016-0701-1
Adhitya J, Wahyuni NY, Zaini E, Fitriani L. Increased dissolution rate of aceclofenac by formation of multicomponent crystals with L-glutamine. Int. J. Appl. Pharm., 16(1), 45–52 (2024) https://doi.org/10.22159/ijap.2024.v16s1.09
Rupal J, Kaushal J, Mallikarjuna SC, Dipti P. Preparation and evaluation of solid dispersions of aceclofenac. Int. J. Pharm. Sci., 1(1), 32–5 (2009) https://doi.org/10.25004/IJPSDR.2009.010108
Lapidus SH, Stephens PW, Arora KK, Shattock TR, Zaworotko MJ. A comparison of cocrystal structure solutions from powder and single crystal techniques. Cryst. Growth Des., 10, 4630–7 (2010) https://doi.org/10.1021/cg1009237
Kavuru P, Aboarayes D, Arora KK, Clarke HD, Kennedy A, Marshall L, et al. Hierarchy of supramolecular synthons: persistent hydrogen bonds between carboxylates and weakly acidic hydroxyl moieties in cocrystals of zwitterions. Cryst. Growth Des., 10, 3568–84 (2010) https://doi.org/10.1021/cg100565a
Afzal H, Abbas N, Hussain A, Latif S, Fatima K, Arshad MS, et al. Physicomechanical, stability, and pharmacokinetic evaluation of aceclofenac–dimethyl urea cocrystals. AAPS PharmSciTech, 22(2), 68 (2021) https://doi.org/10.1208/s12249-021-01938-7
Usha AN, Mutalik S, Reddy MS, Ranjith AK, Kushtagi P, Udupa N. Preparation and in vitro, preclinical and clinical studies of aceclofenac spherical agglomerates. Eur. J. Pharm. Biopharm., 70(2), 674–83 (2008) https://doi.org/10.1016/j.ejpb.2008.06.010
Ahmadi S, Mondal PK, Wu Y, Gong W, Mirmehrabi M, Rohani S. Virtual multicomponent crystal screening: hydrogen bonding revisited. Cryst. Growth Des., 21(10), 5862–72 (2021) https://doi.org/10.1021/acs.cgd.1c00737
Patil SP, Kulkarni AS, Patel SK, Dave RH. Physicomechanical and stability evaluation of aceclofenac–dimethylurea cocrystals. AAPS PharmSciTech, 22(3), 93 (2021) https://doi.org/10.1208/s12249-021-01938-7
Shete AS, Yadav AV, Doijad RC. Screening of aceclofenac for cocrystallization with nicotinamide: theoretical and practical perspective. Indian J. Pharm. Sci., 84(6), 1389–97 (2022) https://doi.org/10.36468/pharmaceutical-sciences.1037
Rusli D, Umar S, Aldi Y, Usman H, Siregar MN, Zaini E. Enhancement of aceclofenac dissolution rate via solid dispersion with hydroxypropyl methylcellulose. Trop. J. Nat. Prod. Res., 9(1), 152–6 (2025) https://doi.org/10.26538/tjnpr/v9i1.22
Sarkar P, Biswas M. Formulation development and in vitro characterization of ternary hydrotropic solid dispersions of aceclofenac. Asian J. Pharm. Clin. Res., 15(9), 174–9 (2022) https://doi.org/10.22159/ajpcr.2022.v15i9.45158
Kumar A, Kumar M. Improvisation of dissolution profile of aceclofenac by using cocrystallization technique. Afr. J. Biomed. Res., 27(4S), 11518–24 (2024) https://doi.org/10.53555/AJBR.v27i4S.5769
Published
How to Cite
Issue
Section
Copyright (c) 2025 Aditay Kumar, Mahesh Kumar
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
